1. Field of the Invention
The present invention relates to a multi-stage method for preparing alkali metal salts of specific 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic esters which starts from malonic ester and does not require isolation of intermediates.
2. Description of Related Art
The preparation of hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic esters, the corresponding tautomers or the alkali metal salts thereof, and also the use thereof as a component in the synthesis of biologically active compounds, is known (WO 2011/018180, WO 2009/036899, J. Chem. Soc., Perkin Trans. 1, 1985, pages 1567 to 1576, Berichte der Deutschen Chemischen Gesellschaft (1911), 44, 1759-1765). However, the known methods have disadvantages as described hereinafter.
WO-A-2012/117015 discloses a method for preparing sodium or potassium salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic esters. However, the method according to WO-A-2012/117015 is not conducted in the presence of a phase transfer catalyst. Moreover, the method in step (ii) uses the expensive component ethyl chloroacetate to azeotrope the aqueous phase. The partial hydrolysis of ethyl chloroacetate leads to high reactant and disposal costs.
WO 2011/018180 describes a preparation of hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic ester starting from malonic ester. The latter is reacted with a haloacetyl chloride compound in the presence of a base (see reaction scheme 1). After addition of water, the desired 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic ester is obtained. The base is selected so as to be capable of deprotonating the malonic ester, as a result of which the enolate of the malonic ester is formed, which is then acetylated by the haloacetyl chloride compound. Suitable bases are especially alkoxides of the general formula M(ORa)b, in which M is Na+, K+, Mg2+, b is 1 or 2 and Ra is methyl or ethyl. Sodium methoxide is specified as preferred. On completion of ring closure, the desired product is obtained together with an inorganic salt which is formed as a by-product (e.g. NaCl if a sodium alkoxide is used as the base).

The removal of the inorganic salt from the reaction mixture, especially when it is NaCl, is achievable only through a very high level of technical complexity, if at all, since the compounds of the formulae (P-I′) and (P-I) are of very good water solubility. Distillation is impossible since the compounds of the formulae (P-I′) and (P-I) decompose at relatively high temperatures with release of CO2. The inorganic salt is therefore not removed. Instead, it is carried over into the subsequent reaction and can only be removed following completion of the further reaction of the compounds of the formulae (P-I′) and/or (P-I).
WO 2009/036899 describes a synthesis of salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic esters, which proceeds from a malonic ester potassium salt and in which the corresponding salt of a 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic ester is prepared using chloroacetic ester and an alkoxide base, e.g. sodium methoxide (see reaction scheme 2). This reaction does not give rise to any inorganic salts which have to be carried forward. However, it is necessary for their removal to completely remove the polar solvent dimethylformamide (DMF) or dimethylacetamide (DMA) used as solvent in step 1. DMF and DMA are both toxic for reproduction and expensive and are very difficult to remove and recycle. A further disadvantage is the use of the expensive monopotassium salt of malonic ester.

Step 1 of the aforementioned reaction is an esterification in which potassium chloride is obtained as a by-product, which is subsequently removed from the reaction mixture by an aqueous wash. In step 2, the ring closure to give the desired compound (Q-II) takes place, and a transesterification may occur therein, so that the product is obtained as a mixture of the compounds of the formulae (Q-II) and (Q-II′). Compounds of the formula (Q-IV) are solids and are commercially available or can be prepared by known methods (cf. J. Am. Chem. Soc. 1944, Nr. 66, p. 1286, EP-A-950653, WO 2008/150487).
The preparation of the product according to the method cited in WO 2009/036899 is industrially disadvantageous since the method proceeds from expensive malonic ester potassium salts of the formula (Q-IV) present in solid form. In the case of industrial preparation, the use of solids as starting materials is fundamentally undesirable, since the technical handling of solids is difficult and more often involves a change of solvent, which overall leads to a considerable technical complexity for performing the reaction.